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MS Society-funded fellow publishes study that examines new class of compounds with the potential to protect against nerve damage and halt MS progression

March 6, 2015

Canadian Study

Background

One of defining characteristics of multiple sclerosis,
particularly in the progressive phase, is the extensive damage that
occurs to axons, or nerve fibres, that are found underneath
the myelin sheath in the central nervous system. This axonal damage is
part of a process called neurodegeneration, and is believed to
result in the permanent neurological deficits and disability that
are seen in progressive MS. While all of the clinically-approved
therapies for MS to date target some aspect of the inflammatory
process that triggers disease relapses, combating the
neurodegeneration and worsening disability of progressive MS
continues to be elusive.

An exciting new study was published this month in Nature Neuroscience
and attempts to address this gap in our understanding. The study,
conducted by postdoctoral fellow Dr. Jeffery Haines – whose
fellowship is jointly funded by the MS Society and Fonds de
Recherche du Québec – Santé (FRSQ) – and colleagues identified a
molecular target that is thought to play a role in the axonal
damage underlying MS and other neurodegenerative disorders. In
addition, they tested a new class of compounds to see whether
they could protect against this damage and halt the progression
of disability.

Specifically, the group examined a protein called CRM1
(chromosome region maintenance protein 1), a molecular “shuttle”
that transports important regulatory proteins out of the nucleus
of nerve cells and into the surrounding gel-like compartment of
the cell, called the cytoplasm. Previous research has shown that
in certain neurodegenerative conditions, CRM1 is produced in
abnormal quantities and forces these regulatory proteins to
inappropriately accumulate in the cytoplasm, where they
contribute to axonal damage. The aim of this study was to
determine if inhibiting CRM1 could have a beneficial therapeutic
role in preventing axonal damage and promoting neuroprotection.

The Study

The authors investigated two molecules that are known to inhibit
CRM1 to determine if they could prevent axonal damage and halt
progression of MS-like disease in mice. Firstly, however, they
examined and compared CRM1 protein content in post-mortem brain
tissue of people with MS versus healthy controls.

Subsequently, the authors induced an MS-like disease in mice and
administered each of the CRM1 inhibitors or an inactive control
drug after mice began to develop characteristic symptoms of MS.
To determine whether the treatment can be used prophylactically
to prevent disease onset and encourage neuroprotection, CRM1
inhibitors were also given before the MS-like disease was induced
in a separate group of mice.

A wide variety of outcomes were measured to test the potential
therapeutic benefits of the CRM1 inhibitors, including:
progression of motor disability, axonal destruction in tissue
samples, myelin repair, and inflammatory activity.

Finally, the authors set out to identify the specific molecular
targets of the CRM1 inhibitors by screening molecules in the
treated nerve cells that were retained in the cell nucleus, where
they would have a neuroprotective effect.

Results

The authors found that CRM1 proteins levels were significantly
higher in the brain tissue of people with MS compared to healthy
controls, indicating that higher levels of this protein are
associated with MS.

When they tested the CRM1 inhibitors in mice with an MS-like
disease, they discovered that the inhibitors halted disease
progression via a two-pronged approach that targets both
neuroprotection and immune function. Specifically, while mice
with MS-like disease developed paralysis of the hindlimbs, CRM1
inhibitors substantially improved motor function in these mice.
Examination of nervous tissue showed that treatment with the
inhibitors prevented further axonal destruction although,
interestingly, this effect was not a result of stimulated repair
of damaged myelin. Treating mice prophylactically was successful
in reducing both disease onset and severity.

The authors also saw fewer inflammatory lesions and a reduction
in the number of harmful immune cells following treatment with
CRM1 inhibitors, both locally around lesions sites and in the
peripheral bloodstream. They noted that the drug did not destroy
or inactivate immune cells; rather, it worked by preventing them
from rapidly multiplying.

Lastly, the authors found that when CRM1 was inhibited, certain
proteins that have been associated with axonal damage in other
disorders were retained in the nuclei of nerve cells, where they
are thought to exert a neuroprotective effect.

Comment

Although therapies that target the immune system and modify the
inflammatory process – termed immunomodulatory therapies – are the mainstay
of treatments used to manage relapsing-remitting MS, they are
nonetheless unable to stop the progression of axonal damage that
leads to lasting disability. This study lays the foundation for a
new approach to potentially combating progressive MS by exploring
a new class of compounds that are both immunomodulatory and
neuroprotective. An added benefit of these compounds is that they
can be administered orally and easily cross the blood brain barrier to enter the central
nervous system, making them promising candidates for drug testing
and validation down the road. A great deal more work needs to be
done, however, before these early but encouraging preclinical
findings can be translated into viable treatment options for
people living with MS.